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. 2023 Feb;123(2):367-380.
doi: 10.1007/s00421-022-05040-z. Epub 2022 Oct 28.

Association between atherogenic risk-modulating proteins and endothelium-dependent flow-mediated dilation in coronary artery disease patients

Andrea Tryfonos  1   2 , Joseph Mills  3 , Daniel J Green  4 , Anton J M Wagenmakers  1 , Ellen A Dawson  1 , Matthew Cocks  5
Affiliations

Association between atherogenic risk-modulating proteins and endothelium-dependent flow-mediated dilation in coronary artery disease patients

Andrea Tryfonos et al. Eur J Appl Physiol. 2023 Feb.

Abstract

Purpose: Endothelial dysfunction is an early and integral event in the development of atherosclerosis and coronary artery disease (CAD). Reduced NO bioavailability, oxidative stress, vasoconstriction, inflammation and senescence are all implicated in endothelial dysfunction. However, there are limited data examining associations between these pathways and direct in vivo bioassay measures of endothelial function in CAD patients. This study aimed to examine the relationships between in vivo measures of vascular function and the expression of atherogenic risk-modulating proteins in endothelial cells (ECs) isolated from the radial artery of CAD patients.

Methods: Fifty-six patients with established CAD underwent trans-radial catheterization. Prior to catheterization, radial artery vascular function was assessed using a) flow-mediated dilation (FMD), and b) exercise-induced dilation in response to handgrip (HE%). Freshly isolated ECs were obtained from the radial artery during catheterization and protein content of eNOS, NAD(P)H oxidase subunit NOX2, NFκB, ET-1 and the senescence markers p53, p21 and p16 were evaluated alongside nitrotyrosine abundance and eNOS Ser1177 phosphorylation.

Results: FMD was positively associated with eNOS Ser1177 phosphorylation (r = 0.290, P = 0.037), and protein content of p21 (r = 0.307, P = 0.027) and p16 (r = 0.426, P = 0.002). No associations were found between FMD and markers of oxidative stress, vasoconstriction or inflammation. In contrast to FMD, HE% was not associated with any of the EC proteins.

Conclusion: These data revealed a difference in the regulation of endothelium-dependent vasodilation measured in vivo between patients with CAD compared to previously reported data in subjects without a clinical diagnosis, suggesting that eNOS Ser1177 phosphorylation may be the key to maintain vasodilation in CAD patients.

Keywords: Atherosclerosis; Coronary artery disease; Endothelial cells; Endothelial dysfunction; Exercise-induced dilation; Flow-mediated dilation.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Positive correlation between flow-mediated dilation (FMD%) and eNOS Ser1177 phosphorylation (peNOS Ser1177) in endothelial cells (ECs) obtained from radial arteries of coronary artery disease patients. Representative images of the immunofluorescence images of peNOS Ser1177 from CAD patients with low and high FMD are shown. AU: arbitrary units EC protein expression data are reported as ratios to human umbilical vein endothelial cells (HUVEC) protein expression
Fig. 2
Fig. 2
Positive correlation between flow-mediated dilation (FMD%) with p16 (a) and p21 (b) protein expression in endothelial cells (ECs) obtained from radial arteries of coronary artery disease patients. Representative images of the immunofluorescence images of p16 (a) and p21 (b) from CAD patients with low and high FMD are shown. AU arbitrary units EC protein expression data are reported as ratios to human umbilical vein endothelial cells (HUVEC) protein expression, p16 cyclin-dependent kinase inhibitor 2A, p21 cyclin-dependent kinase inhibitor 1
Fig. 3
Fig. 3
Positive relations between eNOS Ser1177 phosphorylation with NOX2 (a) and senescence marker p21 (b) of endothelial cells (ECs) obtained from radial artery of coronary artery disease patients. NFκB is correlated with ET-1 (c) and NOX2 (d). AU arbitrary units EC protein expression data are reported as ratios to human umbilical vein endothelial cells (HUVEC) protein expression; NOX2: NADPH oxidase subunit 2, p21 cyclin-dependent kinase inhibitor 1, NFκB nuclear factor kappa-light-chain-enhancer of activated B cells, ET-1 endothelin-1, peNOS phospho-endothelial nitric oxide synthase
Fig. 4
Fig. 4
Positive correlations between senescence and oxidative stress expression of endothelial cells (ECs) obtained from radial artery of coronary artery disease patients. NT expression is related to p16 (a), p21 (b) and p53 (c), NOX2 expression is correlated to p21 (d) and p53 (e), and p21 expression is associated with p53 (f). AU arbitrary units EC protein expression data are reported as ratios to human umbilical vein endothelial cells (HUVEC) protein expression, NT nitrotyrosine, p16 Cyclin-dependent kinase inhibitor 2A, p21 cyclin-dependent kinase inhibitor 1, p53 tumor protein 53, NOX2 NADPH oxidase subunit 2
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